Pharmacokinetic analyses with RUGFIT: an interactive pharmacokinetic computer program

RUGFIT is an interactive computer program to fit polyexponential equations to experimental points without the need of assumptions about the number of exponential terms and without the need of initial parameter estimates. The fitting is performed by iterative stripping minimizing the sum of squared residuals. This procedure leads to multiple model equations describing the profile of the y-value in time, that are compared with the test of Boxenbaum et al. The examples analysed in this paper are: a plasma decay curve after an intravenous bolus injection and one after an oral gift, a dA/dt versus time curve with a lag time and a curve possibly reflecting an entero-hepatic recirculation. The outcomes are, where possible, compared with the outcomes obtained with the computer programs CFT3, NONLIN, and NONLINEAR (SPSS). The latter three programs sometimes run into a local minimum, as the outcomes obtained with RUGFIT were close to the best ones obtained with the other programs. The analyses with RUGFIT show that a choice of an inadequate model equation can lead to a marked error in the value of the area under the curve that may result in a marked error of, for instance, the bioavailability. The procedures of RUGFIT are illustrated in the Appendix. RUGFIT also contains options to calculate microparameters, to simulate dosage regimes, to calculate exponents and intercepts from rate constants and to analyse time effect relationships.     

A new method for multi-compartment pharmacokinetic analysis: The eigenvector decomposition principle

Summary It is well known in pharmacokinetics that exponential changes in blood concentrations of a drug are not related directly to the properties of the compartments that make up the system under study. A mathematical analysis is presented that permits treatment of the exponential components in a manner analogous to that of the hypothetical compartments. A simple treatment of cumulation processes in the central compartment is done to avoid full analysis of the system. For the circumstance when elimination is confined to the central compartment, total accumulation in the system and the exact volume of distribution are calculated from the blood concentration curve after a single i.v. injection. The method reduces complex accumulation calculations to the simplicity of single compartment formulae.     

Nonlinear least-squares regression analysis by a simplex method using differential equations containing Michaelis-Menten type rate constants

Computer curve fittings were carried out to observed data as well as theoretically generated plasma concentrations of several drugs, using differential equations which contained nonlinear Michaelis-Menten type rate constants to discuss problems of initial parameter estimation in pharmacokinetic analysis. Calculation based on two different algorithms, each carried out by using SIMP (simplex method) and NONLIN (modified Gauss-Newton method) produced similar results. However, occasional divergence or unreasonable solutions occurred in a later case, when assumed values of Km and Vmax were used as initial parameters. A combined use of SIMP and NONLIN in which calculated values by SIMP were used as initial values for NONLIN, was shown to be effective to analyse plasma concentration data of indocyanine green bearing difficulty in estimating initial values. It is suggested that the successive method is useful for the curve fitting of plasma concentration with nonlinear pharmacokinetic rate processes.     

High performance liquid chromatographic analysis of rabeprazole in human plasma and its pharmacokinetic application

A simple and sensitive HPLC method for the analysis of rabeprazole in plasma is described using UV detection in the presence of lorazepam as the internal standard. Rabeprazole and lorazepam were extracted with ethyl ether and quantitated using a reverse-phase C(18) column. The method was specific as there were no interfering peaks in the human plasma eluting at the retention times of rabeprazole and lorazepam. The method was fully validated in human plasma for the concentration range of 20.0-1000.0 ng/ml. The correlation coefficients were greater than 0.999. Extraction recoveries were 72.3% for the drug and 79.1% for the internal standard. The method was simple, reliable, and accurate for the quantitation of rabeprazole in human plasma. The same plasma samples, which were collected in healthy male volunteers administered a 20 mg tablet of Pariet, were analyzed by HPLC and LC/MS/MS. As a result of that, there was no significant difference between pharmacokinetic parameters. The suitability of HPLC method for pharmacokinetic studies was verified by determining the relevant pharmacokinetic parameters.     

盐酸曲美他嗪在人体内药物动力学研究分析

目的建立液相色谱—串联质谱法(LC-MS/MS)测定血浆中盐酸曲美他嗪浓度的方法,并研究其药动学行为。方法选取我院2007年2月至2009年2月18名健康成年人作为药物试验对象,均单剂量口服盐酸曲美他嗪40mg后,采用液相色谱—串联质谱法(LC-MS/MS)测定血药浓度,应用AIC法判断房室模型,并利用DAS软件计算药动学参数。结果主要药动学参数:Cmax为(126.11±20.18)μg/L,tmax为(1.78±0.65)h,t1/2Ke为(5.87±0.79)h,Ke为(0.13±0.03)h,V/F为(4.00±0.59)L/kg,CL/F为(0.49±0.09)L.h-1.kg-1,AUC0-24为(1208.79±198.36)μg.h-1.L-1,AUC0-∞为(1304.46±224.13)μg.h-1.L-1。结论该分析方法简单、快速、准确、精密度高,适用于人体中盐酸曲美他嗪浓度的测定。盐酸曲美他嗪的血浆药动学参数与国内外文献报道基本一致。     

MODFIT: a pharmacokinetics computer program

This paper presents a computer program, MODFIT, written in FORTRAN, primarily for use on the Digital Equipment Company VAX series computers for the mathematical analysis of concentration-time data. Drug data generated from biological fluids and tissues may be fitted by a variety of different models. For many models, parameter starting estimates are program generated prior to automatic nonlinear regression analysis using a modified Davidon-Fletcher-Powell algorithm. The output of results is extensive and plotting facilities are available. Explicit and differential equation models may be fitted to single dose data and simulations using all models (single or repeat dose) may be employed to generate drug concentration-time data with plotting output. The package has been tested on numerous data with no problems regarding local function minima. Some comparisons with existing programs have been made and MODFIT compares well with respect to robustness, efficiency, and ease of use.     

Optimisation of sampling windows design for population pharmacokinetic experiments

This paper describes an approach for optimising sampling windows for population pharmacokinetic experiments. Sampling windows designs are more practical in late phase drug development where patients are enrolled in many centres and in out-patient clinic settings. Collection of samples under the uncontrolled environment at these centres at fixed times may be problematic and can result in uninformative data. Population pharmacokinetic sampling windows design provides an opportunity to control when samples are collected by allowing some flexibility and yet provide satisfactory parameter estimation. This approach uses information obtained from previous experiments about the model and parameter estimates to optimise sampling windows for population pharmacokinetic experiments within a space of admissible sampling windows sequences. The optimisation is based on a continuous design and in addition to sampling windows the structure of the population design in terms of the proportion of subjects in elementary designs, number of elementary designs in the population design and number of sampling windows per elementary design is also optimised. The results obtained showed that optimal sampling windows designs obtained using this approach are very efficient for estimating population PK parameters and provide greater flexibility in terms of when samples are collected. The results obtained also showed that the generalized equivalence theorem holds for this approach.     

Netilmicin in the neonate: pharmacokinetic analysis and influence of parenteral nutrition

Objective The aim of this study was to investigate the impact of parenteral nutrition on netilmicin pharmacokinetics in critically ill neonates during the first week of life. Method A total of 200 neonates (gestational ages 26.4–41 weeks) treated with netilmicin (4–5 mg/kg in extended dosing intervals) for postnatal sepsis in the first week of life received either fluid therapy or parenteral nutrition. Netilmicin peak and trough serum concentrations were monitored and netilmicin pharmacokinetic parameters were compared with and without parenteral nutrition. Results There were no statistically significant differences between the pharmacokinetic parameters of netilmicin (volume of distribution, elimination half-life, clearance) in critically ill neonates >32 weeks during the first week of life that received either fluid therapy or parenteral nutrition. For neonates <32 weeks this comparison was not feasible as the majority were parenterally fed. Conclusion Provision of parenteral nutrition (versus fluid therapy) in critically ill neonates >32 weeks did not significantly affect netilmicin pharmacokinetics and therefore does not require modification of recommended netilmicin dosage regimens.     

Comparative pharmacokinetic analysis of a novel sustained release dosage form of valproic acid in dogs

A new sustained release dosage form of valproic acid (VPA) was developed. The new sustained release dosage form was administered (twice, with and without food) to five dogs in comparison to a standard tablet (Depakine, Labaz) and an i.v. preparation of the drug. Drug level monitoring in the plasma was performed by a GLC assay. Results indicate that the sustained release formulation exhibited a more prolonged and uniform absorption rate, yielded more sustained plasma levels after ingestion, and showed an overall bioavailability of 0.84 (95 per cent C.I. = 0.72, 0.96) relative to an equivalent dose of a conventional tablet.     

Experiences in the application of NONMEM to pharmacokinetic data analysis

Ethical issues arising from the use of patients in medical research have stimulated pharmacokinetic research in population kinetics, which requires only a few concentration samples of each individual. Using historical maprotiline data, the new approach of population kinetics was investigated and compared to individually estimated kinetics. Two different population kinetic methods were applied. The naive approach, a quick and dirty method, was compared to the nonlinear mixed-effects method, which was applied by the NONMEM package. Based on the results we obtained from actual maprotiline data as well as from simulated data, NONMEM is a reasonable tool for the estimation of population pharmacokinetic parameters. The main advantage of NONMEM over the naive approach lies in the possibility of obtaining standard deviations of random effects related to the variability between subjects.     

临床药代动力学和药效动力学研究中的采样优化方法

采样优化方法在临床药代动力学和药效动力学研究中受到广泛关注.本文综述了D优化法、多元线性回归法、基于最大后验贝叶斯估算法(MAPB)的有限采样法等的原理、步骤及优缺点,并总结了各方法在采样优化估算中每一步骤的特点.本文也列举了重要的应用实例,介绍了可实现其估算分析的统计软件.     

Determination of nifeviroc, a novel CCR5 antagonist: application to a pharmacokinetic study

Nifeviroc is a novel CCR5 antagonist used for the treatment of HIV type-1 infection. A LC-ESI-MS/MS method for the determination of nifeviroc in human plasma was developed and validated. The calibration curve (r² = 0.9993) of nifeviroc was established at the range of 1.924-2935 μg L⁻¹. The intra- and inter-day precisions (RSD%) were all less than 7%, and the accuracies at three concentration levels were all within 100 ± 5%. This validated method was then successfully applied to a pharmacokinetic study in health Chinese volunteers.     

Methodological approaches to the population analysis of toxicity data

Toxicokinetics is the assessment of systemic exposure in toxicity studies, in which pharmacokinetic data are generated, either as an integral component in the conduct of the nonclinical toxicity studies or in specially designed supportive studies, in order to assess systemic exposure. The data may be used in the interpretation of toxicity findings and contribute to the assessment of the relevance of these findings to clinical safety. Data may be obtained from all animals in a toxicity study, in representative subgroups, in satellite groups or in separate studies. Applying a mixed effects modelling approach in toxicokinetics offers many advantages over the current approach of having satellite groups. Sparse samples for measuring drug/metabolite concentration are collected in all main animals in the majority of studies where toxicological findings are obtained. Such sampling is unlikely to distress the animals, disturb the conduct of a toxicological study or affect the outcome of the study. Many of the outcome measures in toxicological studies are categorical in nature. For example, lesions may be scored on a one to four scale, from none to severe. The analysis of such data is usually carried out using a general mixed modelling approach. We have implemented such models in a nonlinear mixed effects modelling framework which allows us to relate pharmacokinetic response to outcome. A case study is used to illustrate the principles of general mixed effects modelling in toxicokinetics.     

LC-ESI-MS法测定人血浆中紫杉醇的浓度及其在药代动力学中的应用(英文)

建立了一种灵敏度高、特异性好的高效液相色谱-电喷雾质谱法 (LC-ESI-MS) 测定人血浆中紫杉醇浓度的方法。采用一步液液萃取法进行血浆样品预处理, 提取液为甲基叔丁基醚, 内标选用炔诺酮。色谱柱为Zorbax SB-C18 柱 (100 mm×2.1 mm, 3.5 μm, Agilent), 流动相为甲醇-0.2 mmol/L甲酸铵缓冲盐溶液 (包含0.1%甲酸), 采用梯度洗脱。选择离子监测 (SIM) 的目标离子为紫杉醇的[M+Na]+ m/z 876.5和内标的[M+H]+ m/z 299.4。方法学验证表明线性范围是1.0-400 ng/mL (r>0.998), 最低定量限为1.0 ng/mL, 方法的批内和批间精密度都小于9.0%, 准确度在6.8%以内。此方法已成功应用于紫杉醇脂质体注射液在患者体内的药动学研究。     

Specificity of pharmacokinetic modeling of nanomedicines

Nanomedicines have been developed for more than four decades to optimize the pharmacokinetics (PK) of drugs, especially absorption, distribution, and stability in vivo. Unfortunately, only a few drug products have reached the market. One reason among others is the lack of proper PK modeling and evaluation, which impedes the optimization of these promising drug delivery systems. In this review, we discuss the specificity of nanomedicines and propose key parameters to take into account for future accurate PK evaluation of nanomedicine. We believe that this could help these innovative drug products to reach to market and change the fate of many diseases.     

Analysis of pharmacokinetic data using parametric models—1: Regression models

This is the first in a series of tutorial articles discussing the analysis of pharmacokinetic data using parametric models. In this article, the purposes of modelling are discussed; regression models for individuals and populations are defined; and structural and variance models are discussed as the two required submodels of the overall regression model. Topics of future articles are: point estimates of parameters; interval estimates of parameters; model criticism and choosing among contending models; population kinetic models and estimation; and elements of optimal design.Work supported in part by NIH Grant GM 26676, and GM 26691.     

Electron-capture gas chromatographic determination of loprazolam in plasma and a pharmacokinetic application

A sensitive and specific gas chromatographic method, using an electron capture detector, for the measurement of plasma concentrations of loprazolam (HR-158) is described. Retention times of the hydrolysis product of loprazolam (2-amino-2'-chloro-5-nitrobenzophenone) and of the internal standard (2-amino-2'-fluorobenzophenone) were, respectively, 9 and 7 minutes. The sensitivity of the assay was 1.0 ng ml-1 of plasma, and for drug concentrations ranging from 1.0 to 15 ng ml-1 the mean recovery from plasma was 94.4 per cent and the mean coefficient of variation 9.8 per cent. This method was used to determine some pharmacokinetic parameters of loprazolam after administration of 2 X 1 mg capsule doses to nine healthy, fasted volunteers. The mean t 1/2 was 6.4 h, mean AUC infinity 65.42 ng.h ml-1, and the mean clearance 0.51 l min-1.     

Pharmacodynamic analysis between plasma level and inhibition of acid output after administration of a new histamine H2-receptor antagonist (Z-300) in dog

1. The relationship between plasma levels of a new H₂-receptor antagonist, Z-300, and an active sulphoxide metabolite, and inhibitory effects on gastric acid secretion after intravenous or oral administration to dog have been examined. After both routes of administration, Z-300 in plasma eliminated with two phases, and the terminal half-lives were 2 h. The level of sulphoxide in plasma reached a maximum at 0.6-0.7 h after administration, then subsequently eliminated with a half-life of 6 h. 2. The maximal pharmacological effect of inhibition of gastric acid secretion (90-91%) was observed at 2 h (i.v.) and 6 h (p.o.), and the action persisted until 7 h after administration. 3. Since there was no correlation between plasma levels of Z-300 and pharmacological effects, the pharmacological effects were calculated by pharmacodynamic model including the effect compartment. The inhibition of acid output could be calculated by the amounts of Z-300 and sulphoxide corrected by pharmacological efficacy in the effect compartment. 4. These findings suggest that Z-300 contributes to the rapid appearance of the pharmacological effects in dog, whereas the sulphoxide, which eliminates slowly in plasma, contributes to duration.     

Evaluation of a pharmacokinetic interaction between valsartan and simvastatin in healthy subjects

ABSTRACT

Objective: The potential for a pharmacokinetic drug interaction between valsartan, an antihypertensive drug, and simvastatin, a lipid-lowering agent, was investigated in this study. This was an open-label, multiple-dose, randomized, three-period, cross over study in 18 healthy subjects. Each subject received one 160?mg valsartan tablet or one 40?mg simvastatin tablet or co-administration of valsartan (160?mg) and simvastatin (40?mg) tablets for 7 days, with a 7?day inter-dose washout period. The steady-state pharmacokinetics of valsartan, simvastatin β?hydroxy acid (active metabolite of simvastatin) and simvastatin (pro-drug) were determined on day 7 of each dosing period.

Results: The results were interpreted based on the point estimates and the 90% confidence intervals.italic> These results indicated that the area under the curve of plasma concentration from 0 to 24 hours (AUC_(0–24)) of valsartan, simvastatin β?hydroxy acid and simvastatin was increased by 14%, 19%, and 23%, respectively, with the combination treatment. In addition, the maximum concentration (C_max) of valsartan and simvastatin β?hydroxy acid was increased by 10% and 22%, respectively, and the C_max of simvastatin was decreased by 26% with the combination treatment. All treatments were safe and well tolerated.

Conclusions: Based on the wide therapeutic dosage ranges of valsartan and simvastatin, and the highly variable pharmacokinetics of three analytes, the observed differences in the exposure and C_max of valsartan, simvastatin β?hydroxy acid and simvastatin in the combination treatment are unlikely to be of clinical relevance.     

Characterization and pharmacokinetic analysis of aerosolized aqueous voriconazole solution

Invasive fungal infections in immunocompromised patients have high mortality rates despite current treatment modalities. This study was designed to evaluate the suitability of an aqueous solution of voriconazole solubilized with sulfobutyl ether-β-cyclodextrin for targeted drug delivery to the lungs via nebulization. A solution was prepared such that the inspired aerosol dose was isotonic with an acceptable mass median aerodynamic diameter of 2.98 μm and a fine particle fraction of 71.7%. Following single and multiple inhaled doses, high voriconazole concentrations were observed within 30 min in the lung tissue and plasma. Drug solubilization with sulfobutyl ether-β-cyclodextrin contributed to the rapid and high drug concentrations in plasma following inhalation. Maximal concentrations in the lung and plasma were 11.0 ± 1.6 μg/g wet lung weight and 7.9 ± 0.68 μg/mL, respectively, following a single inhaled dose with a corresponding tissue/plasma concentration ratio of 1.4 to 1. Following multiple inhaled doses, peak concentrations in lung tissue and plasma were 6.73 ± 3.64 μg/g wet lung weight and 2.32 ± 1.52 μg/mL, respectively. AUC values in lung tissue and plasma were also high. The clinically relevant observed pharmacokinetic parameters of inhaled aqueous solutions of voriconazole suggest that therapeutic outcomes could be benefitted through the use of inhaled voriconazole.